Generalizable Molecular Switch Designs for In Vivo Continuous Biosensing

• DOI: 10.1021/acs.accounts.4c00721
• Publication Date: 2025-02-15T17:58:06Z
• Authors: Jason Saunders; Ian A. P. Thompson; Hyongsok Tom Soh
• Keywords: Molecular switch

ConspectusContinuous biosensors have the potential to transform medicine, enabling healthcare be more preventative and personalized as compared current standard of reactive diagnostics. Realizing this transformative requires that can function continuously in vivo without sample preparation deliver molecular specificity, sensitivity, high temporal resolution. Molecular switches stand out a promising solution for creating such sensors continuous detection many different types molecules. are target-binding receptors designed binding causes conformational change switch's structure. This structure switching induces measurable signal via reporters incorporated into switch, highly specific, label-free sensing. However, there remains an outstanding need generalizable switch designs adapted wide range targets.In Account, we chronicle work our lab has done develop allow rapid development high-performance across broad biomarkers. Pioneering efforts toward switch-based biosensing employed aptamers─nucleic acid-based with sequence-specific target affinity. most these early demonstrations relied upon aptamers intrinsic structure-switching capabilities. To accelerate aptamer design targets, applied rational knowledge aptamer's engineer functionality pre-existing aptamers. Our contained several structural parameters enabled us easily tune sensitivity kinetics resulting switches. Using rationally switches, demonstrated optical cortisol dopamine at physiologically relevant concentrations complex media. In effort move beyond well-characterized properties, developed high-throughput screening method allowed simultaneously screen millions candidates derived from single find sensitive any prior parent aptamer.In subsequent work, reasoned could enhance ability broader by leveraging other classes besides Antibodies offer excellent affinity specificity but lack capacity switching. We therefore set strategies augment antibodies act diverse properties. combined both antibody capabilities chimeric 100-fold enhanced protein improved interferent-rich samples. second design, competitive immunoassay-inspired scheme behavior minutes-scale resolution nanomolar sensitivity. used antibody-switch demonstrate first directly whole blood. Together, advances expanded capability rapidly new biosensors, thereby increasing opportunities track health biomarkers medicine.